A high-fat diet induces a microbiota-dependent increase in stem cell activity in the Drosophila intestine

Abstract

Over-consumption of high-fat diets (HFDs) is associated with several pathologies. Although the intestine is the organ that comes into direct contact with all diet components, the impact of HFD has mostly been studied in organs that are linked to obesity and obesity related disorders. We used Drosophila as a simple model to disentangle the effects of a HFD on the intestinal structure and physiology from the plethora of other effects caused by this nutritional intervention. Here, we show that a HFD, composed of triglycerides with saturated fatty acids, triggers activation of intestinal stem cells in the Drosophila midgut. This stem cell activation was transient and dependent on the presence of an intestinal microbiota, as it was completely absent in germ free animals. Moreover, major components of the signal transduction pathway have been elucidated. Here, JNK (basket) in enterocytes was necessary to trigger synthesis of the cytokine upd3 in these cells. This ligand in turn activated the JAK/STAT pathway in intestinal stem cells. Chronic subjection to a HFD markedly altered both the microbiota composition and the bacterial load. Although HFD-induced stem cell activity was transient, long-lasting changes to the cellular composition, including a substantial increase in the number of enteroendocrine cells, were observed. Taken together, a HFD enhances stem cell activity in the Drosophila gut and this effect is completely reliant on the indigenous microbiota and also dependent on JNK signaling within intestinal enterocytes. High-fat diets have been associated with a plethora of morbidities. The major research focus has been on its effects on obesity related disorders, mostly omitting the intestine, although it is the organ that makes the first contact with all diet components. Here, we aimed to understand the effects of HFD on the intestine itself. Using Drosophila as a model, we showed that a HFD and more specifically, trigylcerides with saturated fatty acids, induced a transient activation of intestinal stem cells. This response completely depended on the presence of an intestinal microbiota, as in germ free flies this reaction was completely abolished. Mechanistically, we found that HFD induces JNK signaling in enterocytes, which triggers production of the cytokine upd3. This ligand of the JAK/STAT pathway, in turn activates STAT signaling in intestinal stem cells, leading to their activation. All these components of the JNK- and JAK/STAT-pathways are necessary for a HFD to lead to increased stem cell production. Moreover, HFD changed both, composition and abundance of the microbiota. As fecal transfer experiments failed to recapitulate the HFD phenotype, we assume that the increased bacterial load is the major cause for the HFD triggered stem cell activation in the intestine.